Single centre study of using bendamustine in the treatment of B-cell malignancies

Objective: To evaluate the experience of bendamustine in the treatment of B-cell malignancies at a tertiary care centre.Methods: The retrospective descriptive analysis included data of all adult patients with B-cell malignancies treated with bendamustine from 2009 to 2011 at the Aga Khan University Hospital, Karachi. Data was analysed using SPSS 17.0. Frequencies and percentages were computed for baseline characteristics, responses and toxicities.Results: Of the 19 patients 15 (79%) were males and 4 (21%) were females.The mean age was 59.53+/-12.14 (with a range of 46-86). Eight (42%) had follicular lymphoma, 6 (32%) had mantle cell lymphoma, 2 (11%) had diffuse large B-cell lymphoma, and 3 (16%) had chronic lymphocytic leukaemia. Four (21%) patients experienced grades 3 and 4 cutaneous toxicities. Eight (42%) patients were treated with bendamustine as first-line therapy. Six of them (75%) were included for response evaluation; 3 (50%) had complete response, and 3 (50%) had partial response. Eleven (58%) patients had relapsed disease out of which 3 (27.27%) had complete response, and 7 (63.63%) had partial response, whereas 1 (9%) had disease progression.CONCLUSION: Bendamustine given as monotherapy or in combination is safe and useful in the treatment of patients with B-cell malignancies

Studies on new substituted pyridazinones: synthesis and biological evaluation

We report herein the synthesis and pharmacological evaluation of a new series of 6-aryl-2-(imidazol1-yl/1,2,4-triazol-1-yl)-2-methyl-4,5-dihydro-(2H)-pyridazin-3-one (3a-j) as potential anticonvulsant and antitubercular agents. The title compounds were prepared by reacting 6-aryl-4,5-dihydro-(2H)- pyridazin-3-one (2a-e) with formaldehyde and secondary cyclic amine imidazole or 1,2,4-triazole as per Mannich reaction. Anticonvulsant activity of pyridazinone derivatives was tested at 50 mg.kg-1 dose level against maximal electroshock (MES), isoniazid (INH, 250 mg.kg-1) and pentylenetetrazole (PTZ at 80 mg.kg-1) induced seizure methods. Phenytoin sodium (25 mg.kg-1) and sodium valproate (100 mg. kg-1) were used as reference drugs for comparison purpose. In-vitro antitubercular activity was tested by Microplate Alamar Blue assay (MABA) method and the results were compared with clinically used antitubercular agents such as INH, Pyrazinamide (PZA) and Streptomycin (STM). None of the screened compounds were found to be neurotoxic at a dose level of 100 mg.kg-1. All the screened compounds (3a-j) significantly reduced the MES, INH and PTZ induced convulsions and thus showed good anticonvulsant activity. The minimum inhibitory concentration (MIC) of the title compounds against M. tuberculosis ranged from 1.6 µg/mL to 6.25 µg/mL in comparison to INH, PZA (3.125 µg/mL) and STM (6.25 µg/ mL) which indicated good antitubercular activity

Temozolomide for relapsed primary CNS lymphoma.

Primary CNS lymphoma (PCNSL) is an aggressive form of non-Hodgkin\u27s lymphoma that accounts for 3% of all primary brain tumours. No clear risk factors for PCNSL in immunocompetent patients are known. The disease is more common in men and in elderly persons. Patients with AIDS who have low CD4+ counts are at the greatest risk for PCNSL. Virtually all PCNSLs in patients with AIDS express an Epstein-Barr virus (EBV)-related genome. PCNSL is less frequently associated with EBV in patients without AIDS. A 42 years old gentleman diagnosed with primary CNS lymphoma with negative serological test for human immunodeficiency virus was initially treated with Modified De Angelis protocol relapsed after treatment. He underwent gamma knife stereotactic surgery which lead to further deterioration clinically and progression of disease on imaging. Later, he was treated with salvage high dose methotrexate, but after completion of six cycles there was a radiological progression of disease. Relapsed disease was further treated with a single agent temozolomide and the disease went in remission

Study Of Phenothiazine On p53 Core Domain Mutant Y220C: Finding The Anti-tumor Activity Of Phenothiazine

The tumor suppressor protein p53 is a transcription factor that plays a key role in the prevention of cancer development. The p53 cancer mutation Y220C induces formation of a cavity on the protein's surface that can accommodate stabilizing small molecules. We have attempted with the help of virtual screening and molecular docking approach using Lamarckian Genetic Algorithm to elucidate the extent of specificity of p53 cancer mutation Y220C towards different class of Phenothiazines (an anti-cancer agent). 

The 393 residue p53 tumor suppressor protein exists in a dynamic equilibrium to form homotetramers. Each chain comprises several functional domains. The N terminal part of the protein consists of the trans-activation domain (residues 1–63) followed by a proline rich region (64– 92). The central (core) domain (p53 core domain) is responsible for binding. The C terminal part of p53 contains the tetramerization domain (residues 326–355) and the negative regulatory domain at the extreme C terminus (363–393), which contains phosphorylation and acetylation sites and regulates the DNA binding activity of p53.

The docking result of the study of 2,000 Phenothiazines demonstrated that the binding energies were in the range of -10.54 kcal/mol to -1.14 kcal/mol, with 8 molecules showing hydrogen bonds with the active site residues (Lys 164). All the selected 2000 inhibitors were selected on the basis of the structural specificity to the enzyme towards its substrate and inhibitors. Our research provides a blueprint for the design of more potent and specific drugs that rescue p53-Y220C

Quasi-static Normal Indentation of a Circular Disk Shaped Miniature Specimen by Rigid Hemispherical-headed Punches

The influence of diameter of rigid hemispherical-headed punches on a circular disk shaped miniature specimen of medium carbon steel has been investigated, in the small punch test. A 3-D finite-element model carried out the computation of the elastic-plastic solution ofdifferent hemispherical rigid punches. The three hemispherical-headed punches were designed and developed to conduct the miniature test. The small. punch test"was conducted on a circular shaped disk (l0.0 mm diameter, 0.5 mm thick), clamped around the periphery and deformed by central load applied by rigid hemispherical indenter. The ABAQUS finite-element software has been used to determine the load vs punch-displacement curves, von-Mises stresses, equivalent plastic strain, contact pressure, logarithmic stresses, load-till failure and full-field displacement in the model have been computed. The finite-element model was validated by comparing with the experimental data for load vs displacement curves. The effect of punch diameter on load vs displacement was observed experimentally as well as by finite-element method. The computational results compared reasonably well with the experimental results

Proptosis of eye: an atypical presentation of prostatic malignancy.

Orbital metastasis is a rare occurrence found only in about 3 - 10% of all prostate cancers. A 72 years male presented with proptosis of the left eye associated with pain, blurred vision and frequent headaches for the past 8 months. Past medical history had symptoms of bladder outflow obstruction for 3 years. MRI brain and orbit with contrast was consistent with a large soft tissue mass in the left frontal region. The mass was surgically excised in order to achieve palliation. Histopathology revealed poorly differentiated malignant neoplasm with immunohistochemistry favoring metastatic prostate carcinoma. Postoperative radiotherapy was administered with a palliative intent. CT scan identified an enlarged prostate with a nodular lesion, abdominal lymphadenopathy and soft tissue density lesion in the apical segment of left lung. Serum PSA level was 149 µg/L. Bone scan was also consistent with metastatic disease

Outcome of febrile neutropenic patients on granulocyte colony stimulating factor in a tertiary care hospital

Introduction: Febrile neutropenia is a relatively frequent event in cancer patients treated with chemotherapy and improvement in absolute neutrophil count (ANC) has been linked directly to improved outcome. Evaluation of granulocyte colony stimulating factors (GCSFs) for treatment has shown reduced incidences of episodes of prolonged neutropenia and protracted hospitalization. To determine absolute neutrophil counts with GCSF in febrile neutropenic cancer patients admitted to a tertiary care centre and to co-relate the improvement in ANC with mortality and hospital discharge.Methods: A prospective cross sectional study was carried at an oncology ward at Aga Khan University hospital from January 2010 to June 2011. All adult patients who were admitted and treated with GCSF for chemotherapy induced febrile neutropenia were included. Multivariable regression was conducted to identify the factors related with poor outcomes.Results: A total of 131 patients with febrile neutropenia were identified with mean age of 43.2 (18-85) years, 79 (60%) being ≤ 50. Seventy-five (57%) had solid tumors and 56 (43%) hematological malignancies, including lymphoma. Fifty seven (43.5%) had an ANC less 100 cells/mm(3), 34 (26%) one between 100-300 cells/mm(3) and 40 (31%) an ANC greater than 300 cells/mm(3). Thirty (23%) patients showed ANC recovery in 1-3 days, and 74(56%) within 4-7 days. Thirteen (10%) patients showed no recovery. The overall mortality was 18 (13.7%) patients. The mean time for ANC recovery seen in hematological malignancies was 6.34 days whereas for solid tumors it was 4.88 days. Patients with ANC /mm(3) were more likely to die than patients with ANC \u3e300 cells/mm(3) by a factor of 4.3. Similarly patients \u3e50 years of age were 2.7 times more likely to die than younger patients.CONCLUSION: Our study demonstrated that use of GCSF, in addition to intravenous antibiotics, in treatment of patients with chemotherapy induced febrile neutropenia accelerates neutrophil recovery, and shortens antibiotic therapy and hospitalization. We propose to risk classify the patients at the time of admission to evaluate the cost effectiveness of this approach in a resource constrained setup

Studies on Chromene based 2, 6-disubstituted-Thiazolo [3,2-B] [1,2,4] Triazole derivatives: Synthesis and Biological Evaluation

In this study, a series of novel chromene based 2,6-disubstituted-thiazolo[3,2-b] [1,2,4] triazole derivatives (7a-g) were synthesized by condensing 5-substituted-1,2,4-traizole-thione (6a-g) using poly phosphoric acid through one pot reaction. The structure of new compounds was supported by 1H NMR, 13C NMR and MS data. The synthesized compounds were evaluated using writhing assays for analgesic and carrageenan-induced rat paw edema method for anti-inflammatory activities respectively. Some of the newly synthesized compounds 7c, 7f and 7g showed very good anti-inflammatory activity with 90.83%, 85.81% and 88.40% protection respectively along with low GI toxicity as compared to standard drug ibuprofen while compounds 7a, 7b, 7d and 7f showed highest analgesic activity with 52.54%, 54.02%, 56.76% and 52.45% protection among them compound 7d showed better protection than standard drug ibuprofen. Keywords: thiazolo-triazoles, Chromene, Anti-inflammatory, Analgesi